What Are Common Inherited Thrombophilias?

Patient Presentation
A 6-month-old female came to clinic for her health maintenance visit. She was growing well physically. Her mother had several questions regarding her normal development which were easily answered. The mother was most concerned because the family history was now positive for her sister (patient’s maternal aunt) having a recent deep venous thrombosis during pregnancy. The aunt’s evaluation showed Factor V Leiden and the mother was in the process of being tested. She wanted to know if the patient should also be tested. The past medical history showed no abnormal bruising/bleeding or other problems with the patient or other family members.

The pertinent physical exam showed a smiling infant with growth parameters in the 75-95% for age. Her examination was normal. The diagnosis of a healthy infant was made. The pediatrician recommended that first the mother finish her own evaluation and re-iterated that there were several things the mother could already do to decrease her own risk of blood clots including being active and a non-smoker. The physician said, “Being pregnant like your sister is also a risk, and one you need to discuss with your doctor and your husband about. Once we know if you have Factor V Leiden then we can talk about the baby’s risks. Usually we wait until the child is older to discuss testing, but we can have you talk with the genetic counselor if you would like to. The good news is that infants and children are at low risk for getting blood clots.”

Thrombophilia is the increased risk of thromboembolic disease due to a disorder. Thrombophilia can be inherited or acquired (such as antiphospholipid syndrome). The risk of thromboembolic events is much lower in children than adults.

At-risk patients should avoid:

  • Dehydration
  • Sitting for prolonged time periods during travel
  • Obesity
  • Smoking
  • Estrogen containing oral contraceptives

Common inherited thrombophilias include:

  • Prothrombin (Factor II mutation)
    • Second most common
    • Genetics: 1-2% prevalence is variable depending on location and ethnic background.
    • Cause: Abnormal point mutation of the prothrombin gene that causes increased levels of prothrombin, the precursor of thrombin.
  • Protein C
    • Relatively common
    • Genetics and epidemiology – 0.2% prevalence of general population. Heterozygous state is most common. Can occur in homozygous state but has severe thromboembolic events mainly in neonatal period.
    • Cause: Protein C becomes activated (activated Protein C = APC) and combines with Protein S. This complex then normally inactivates Factors Va and VIIIa. Protein C is Vitamin K dependent.
    • Two types:
      • Type 1 – antigen and activity levels are low (quantitative deficiency, 85% of cases)
      • Type 2 – antigen levels are normal and activity levels are low (qualitative deficiency, 15% of cases)
  • Protein S
    • Relatively uncommon
    • Genetics and epidemiology – 0.03-.13% prevalence of general population. Heterozygous state is most common. Can occur in homozygous state but has severe thromboembolic events mainly in neonatal period.
    • Cause: Free Protein S combines with Protein C. This complex then normally inactivates Factors Va and VIIIa. Protein S is Vitamin K dependent. Protein S is 60% protein bound.
    • Three types:
      • Type 1 – free antigen and total antigen is low (quantitative deficiency)
      • Type 3 – free antigen is low but total antigen is normal (quantitative deficiency)
      • Type 2 – normal free and total antigen levels but activity is low (qualitative deficiency)
  • Antithrombin
    • Least common
    • Genetics and epidemiology: 0.02% prevalence of Caucasian population, Autosomal dominant so heterozygous state is most common. Homozygous Type 1 is incompatible with life.
    • Cause: Acts to inhibit several coagulation factors including IIa, IXa, Xa, XIa, and XIIa.
    • Two types:
      • Type I – low antigen and activity levels (quantitative deficiency)
      • Type II – normal antigen but low activity levels (qualitative deficiency)

Learning Point
Factor V Leiden

  • Most common thrombophilia, named for the city of Leiden, Netherlands where it was discovered.
  • Genetics and epidemiology – Prevalence is variable depending on location and ethnic background. 1% in African American population, 2% in Hispanic population and 5% in European background. Mainly occurs in heterozygous state. Homogygotes have a high risk with thrombosis in up to 80/1000.
  • Cause: Factor V Leiden is an abnormal activated Protein C (APC) caused by a point mutation replacing arginine with glutamine at position 1691 which changes the amino acid at position 506 of the protein. Normally APC inactivates coagulation Factor V which then slows down the clotting process and prevents the clots from becoming too large. Is usually inactivated by activated protein C. Factor V Leiden doesn’t allow the APC to work, so the coagulation Factor V continues to allow the clot to grow.
  • Screening is controversial – Prior to a known thrombotic event, many people recommend to wait until children are adolescent age for screening so patients can make informed choices particularly as epidemiology in children is much different than adults. Screening after a thromboembolic event is less clear and most people would evaluate the patient and screen for thrombophilias as this will also help with treatment decisions.

Questions for Further Discussion
1. What are the Vitamin K dependent coagulation factors?
2. What is the role of imaging in evaluation and treatment of thromboembolic events?
3. What is the role of genetic counseling in thromboembolic events?

Related Cases

To Learn More
To view pediatric review articles on this topic from the past year check PubMed.

Evidence-based medicine information on this topic can be found at SearchingPediatrics.com, the National Guideline Clearinghouse and the Cochrane Database of Systematic Reviews.

Information prescriptions for patients can be found at MedlinePlus for these topics: Blood Clots and Bleeding Disorders.

To view current news articles on this topic check Google News.

To view images related to this topic check Google Images.

To view videos related to this topic check YouTube Videos.

Varga EA, Moll S. Prothrombin 20210 Mutation (Factor II Mutation). Circulation. 2004; 110: e15-e18.

Haywood S, Liesner R, Pindora S, Ganesan V. Thrombophilia and first arterial ischaemic stroke: a systematic review. Arch Dis Child. 2005 Apr;90(4):402-5.

Kenet G, Nowak-Gottl U. Venous thromboembolism in neonates and children. Best Pract Res Clin Haematol. 2012 Sep;25(3):333-44.

Heleen van Ommen C, Middeldorp S. Thrombophilia in childhood: to test or not to test. Semin Thromb Hemost. 2011 Oct;37(7):794-801.

Kalpatthi, RV, Kirkland KR, Tarantino CA. Screening for Factor V Leiden Mutation. The Link – Kansas City Mercy Infectious Disease. 2015; April 7(4).


Donna M. D’Alessandro, MD
Professor of Pediatrics, University of Iowa Children’s Hospital

Look at II, III, aVF in this case, and the outcome…..

I just posted this case:

Isolated "Inferior" ST Segment Depression: Not a Sign of Inferior Ischemia

Today I post another case that nicely demonstrates the significance of inferior ST depression.

A middle-aged female presented to the ED with chest pain. It had been intermittent all day.

Here was her first ED ECG with active pain:
There are abnormal ST segments in "inferior" leads, and very subtle STE in aVL, with T-wave inversion.  There are "down-up" T-waves in the inferior leads, which are almost always due to ischemia. 
(Up-down T-waves are sometimes due to hypokalemia - the upright "T" wave is actually a U-wave in these cases.  This is usually in leads V2 and V3.  See these cases for examples)

Isolated ST depression in II, III, and aVF should be considered to be reciprocal to subtle ST elevation in aVL and to indicate that there is occlusion of the Diagonal, Obtuse Marginal, or even the LAD.

Initial troponin I was 0.65 ng/mL.

After she was initiated on ASA/Plavix/Heparin and Nitro, her chest pain resolved. 

Time 40 minutes:
The ST depression is resolved.  "Inferior" T-waves are now fully upright, consistent with reperfusion in the territory of aVL.  Now there are Wellens' waves in anterolateral leads, consistent with reperfusion in the proximal LAD.  This strongly suggests that while the patient was having chest pain, the proximal LAD was occluded.

She remained pain free all night.

It is wise to put these patients on continuous 12-lead ST segment monitoring, as re-occlusion can occur without any chest pain.

Next morning:
Evolution of T-wave inversion confirms Wellens' waves.  There is no doubt that this will be a proximal LAD lesion

Echo showed anteroapical wall motion abnormality.  Troponin I peaked at 2.5 ng/mL.

Angiogram showed 99% thrombotic stenosis with TIMI-II flow in proximal LAD.  It was stented.


At time zero, during maximal chest pain, she had a full proximal LAD occlusion.  After NTG, it opened enough for adequate perfusion, chest pain relief, and T-wave inversion.

Note how subtle this occlusion was: it is only seen by some subtle ST depression in II, III, and aVF and subtle STE in aVL.

Note also that the ischemia was in the LAD territory, but the ST depression was "inferior."

#SettimanaPS15: domenica 24 maggio ultimo giorno, istantanee e progetti per il futuro


Domenica conclusiva per la Settimana del Pronto soccorso di quest’anno. Oggi ancora in alcune piazze e ospedali d’Italia ci saranno incontri con la popolazione per raccontare come funziona l’emergenza: dal lungomare di Crotone in Calabria, ai principali ps toscani, fino alla piazza di Assisi.

Il questi giorni sono state tante le iniziative Simeu: porte aperte nei pronto soccorso; incontri con i ragazzi delle scuole, convegni sui temi più importanti dell’attività dei pronto soccorso, come la cura e l’assistenza per i pazienti fragili, e sui punti critici del sistema, come il sovraffollamento; incontri con la stampa locale e nazionale; presentazione di progetti regionali per migliorare l’efficienza delle cure.

Una prima carrellata di foto sul profilo fb della Società e qui di seguito qualche istantanea.

Acquaviva delle Fonti (Bari)

Porte aperte all’ospedale Gradenigo di Torino

Convegno sulle fragilità sociali al Pronto soccorso – Vercelli












E prima dell’appuntamento per la prossima primavera, la Settimana del pronto soccorso torna in estate a Torino con un appuntamento fuori calendario:




Giovedì 23 luglio, dalle ore 19 a Collegno (To) – Parco della Certosa

Nuova puntata della collaborazione fra Simeu, Società italiana dell’emergenza-urgenza, e Africa Unite, storico gruppo musicale reggae-dub di Pinerolo, da oltre vent’anni al centro della scena musicale alternativa nazionale e oggi prima band del panorama reggae italiano.

Dopo la coproduzione Simeu-Africa Unite del video per il web per un uso responsabile del pronto soccorso, già diffuso in occasione del Congresso nazionale Simeu lo scorso novembre a Torino, Giovedì 23 luglio 2015, gli Africa Unite in concerto al Flowers Festival di Collegno si faranno portavoce del messaggio della Settimana Simeu del Pronto Soccorso, la manifestazione annuale ideata e realizzata da Simeu per favorire il confronto fra professionisti della sanità e popolazione in occasioni lontane dalla stringente necessità dei momenti di urgenza sanitaria, con lo scopo di migliorare, insieme, il servizio sanitario di emergenza. Il concerto di Torino costituisce una tappa importante nel tour di Africa Unite per il lancio del loro nuovo disco dal titolo: Punto di partenza.

In occasione del concerto sarà organizzato un breve incontro fra il pubblico e i rappresentanti della Società scientifica, verrà distribuito materiale informativo sul corretto funzionamento del Pronto soccorso e sarà proiettato il video prodotto da Simeu e Africa Unite su un uso responsabile del pronto soccorso.

FLOWERS FESTIVAL è un nuovo festival musicale che si tiene a Collegno (To), dal 4 al 30 luglio 2015, nel Parco della Certosa, parco urbano di 400.000 mq, in un’area attrezzata per 5000 spettatori. La rassegna, che si tiene nell’exCortile della Lavanderia del Manicomio di Collegno, ospiterà nomi importanti della scena musicale internazionale, fra cui Patty Smith e Goran Bregovich. Flowers Festival è organizzato l’Associazione Culturale Hiroshima Mon Amour, che ha dato vita negli anni ad alcuni dei principali festival musicali piemontesi, tra cui Traffic, Pellerossa ed Extrafestival. La realizzazione della rassegna si avvale del sostegno della Città di Collegno e della Regione Piemonte e del patrocinio della Città Metropolitana Torino. Il calendario completo del festival su http://www.hiroshimamonamour.org/.

Wo gehobelt wird…

Verletzungen sind im Rahmen der Thoraxkompression häufig. Sogar häufiger als wir dachten, sagen Pathologen aus Lubljana.

Frequency and number of resuscitation related rib and sternumfractures are higher than generally considered.

Resuscitation. 2015 Mar 12


In Slowenien wird verpflichtend eine Autopsie durchgeführt, wenn  die Todesursache unnatürlich, oder nicht zweifelsfrei geklärt ist. Am Institut für forensische Medizin von Ljubljana untersuchten Kralle und seine Co-Autoren die 2148 der 10.501 Autopsien der Jahre 2004-2013, bei denen eine CPR durchgeführt wurde auf knöcherne Verletzungen des Thorax (SCI – skeletal chest injuries) und andere Verletzungen.

Präklinischen Reanimationsmaßnahmen werden zumeist durch ein arztbesetztes ACLS-Team durchgeführt.

Von den 2148 Fällen waren 1253 präklinisch (OHCA-out of hospital cardiac arrest), 611 innerklinisch (IHCA- in hospital cardiac arrest) und 234 an beiden Orten im Sinne eines Transportes und Aufnahme unter Reanimation erfolgt.

Miller hatte noch im letzten Jahr ein Review vorgestellt, das eine Verletzungshäufigkeit von 31,2% für die Rippen- und 15,1% für die Sternumfraktur darstellte. Dies sieht bei den Kollegen deutlich anders aus:

Bildschirmfoto 2015 05 24 um 03 43 10

Hier sehen wir eine klar altersabhängige Häufigkeitsverteilung, die ab dem 50.Lebensjahr mühelos die 80%-Marke für knöcherne thorakale Verletzungen überschreitet. Dabei finden die, wie zu erwarten, im mittleren Throax-Drittel statt.

Bildschirmfoto 2015 05 24 um 03 56 46

Zugleich lässt sich mit Steigerung der Intensität der Herzdruckmassage über die Jahre der Guidelineanpassungen nur ein tendenzieller Anstieg der Verletzungshäufigkeit darstellen, der keine statistische Signifikanz erreicht.

Bildschirmfoto 2015 05 24 um 03 59 01

134 wurden mit einem LUCAS-System reanimiert. in einem logistischen Regressions-Modell ließ sich keine Änderung der Gesamthäufigkeit von skeletalen Verletzungen nachweisen. Lediglich die Subgruppe der Frauen mit Sternumverletzungen zeigte eine Häufigkeitsveränderung mit einer odds ratio von immerhin 2,25 (95% CI 1,83-2,85, p<0,001).

Eine Relevanz dieser Verletzungen für das Überleben war mit wenigen Ausnahmen nicht gegeben.

36 Patienten wiesen iatrogene Verletzungen auf, die nach Einschätzung der Pathologen zum Tod beigetraen haben. Bei 30 dieser Patienten war es zu Blutungen von mehr als 500ml gekommen, sowohl durch Leberrupturen, als auch Milzrupturen oder dislozierte Sternum oder Rippenfrakturen. Als Einzelfälle ließen sich multiple Organschäden, ein Spannungspneu, eine Aortenruptur, sowie eine Magenruptur nachweisen.

Insgesamt bezeichnen wird in dieser Arbeit die Häufigkeit bedeutsamer Verletzungen mit 1,85% angegeben.



Die Herzdruckmassage ist bei einem zu renimierenden Patienten ohne Kreislauf alternativlos. Sie geht aber regelhaft mit knöchernen Verletzungen einher, die aber zumeist ohne Bedeutung für den Reanimationserfolg sind. Möglicherweise höhergradige Verletzungen müssen wir aber vor Augen haben, um ggf. auch diese Schäden zu mildern.